Experimental study for the treatment of neuronal degeneration in lysosomal storage diseases by modification of autophagy

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591511
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Osaka City University
• Principal Investigator: TANAKA Akemi 大阪市立大学, 医学(系)研究科(研究院), 准教授 (30145776)
• Co-Investigator(Kenkyū-buntansha): NAEDA Mitsuyo 公益財団法人先端医療振興財団, 上級研究員 (40122080) ; SETO Toshiyuki 大阪市立大学, 大学院医学研究科, 講師 (60423878) ; SAWADA Tomo 大阪市立大学, 大学院医学研究科, 研究員 (60585991)
• Project Period (FY): 2011 – 2013
• Keywords: ライソゾーム病 / 神経変性 / オートファジー / 経口治療薬

Research Abstract

Autophagy is an important factor in the degeneration of neuronal cells of lysosomal storage diseases. We did an experimental study of modifying the autophagy to treat the neurodegeneration in the brain of the mucopolysaccharidosis type II model mouse (IDS-KO).
SCMAS staining of the brain of IDS-KO showed abnormal stimulation of autophagy in various cells especially in neuronal cells, which began from around 6 weeks old IDS-KO. At age 25 weeks, abnormal inclusion bodies appeared in the cytoplasm of neuronal cells of IDS-KO brain, which was not existed at age 20 weeks. We administered chloroquine to IDS-KO orally from 4 weeks old until the examination at 25 weeks old, which findings of the brain were similar to those of 20 weeks old IDS-KO. The result suggested that the inhibition of autophagy could suppress the disease progression in the brain of IDS-KO.

Research Products

• [Journal Article] Impact of Enzyme Replacement Therapy and Hematopoietic Stem Cell Therapy on Growth in Patients with Hunter Syndrome (2014)
  • Author(s): Patel P, Suzuki Y, Tanaka A, Yabe H, Kato S, Shimada T, Mason RW, Orii KE , Fukao T, Orii T, Tomatsu S
  • Journal Title: MGM reports Volume: 1 Pages: 184-196
  • Peer Reviewed
• [Journal Article] Expression of single-stranded DNA and p53 in delayed neuronal death after transient ischemia in the gerbil hippocampus (2013)
  • Author(s): Maeda M, Suwa F, Takemura A, Toda I, Uemura M, Kuwabara A, Nisijima I.
  • Journal Title: J Osaka Dent Univ Volume: 47 Pages: 31-40
  • Peer Reviewed
• [Journal Article] Current diagnosis and management of mucopolysaccharidosis VI in the Asia-Pacific region (2012)
  • Author(s): Hwu WL, Okuyama T, But WM, Estrada S, Gu X, Hui J, Kosuga M, Lin SP, Ngu LH, Shi H, Tanaka A, Thong MK, Wattanasirichaigoon D, Wasant P, McGill J
  • Journal Title: Mol. Genet. Metab Volume: 107 Pages: 136-44
  • Peer Reviewed
• [Journal Article] Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II : A nationwide survey in Japan (2012)
  • Author(s): Tanaka A, Okuyama T, Suzuki Y, Sakai N, Takakura H, Sawada T, Tanaka T, Otomo T, Ohashi T, Ishige-Wada M, Yabe H, Ohura T, Suzuki N, Kato K, Adachi S, Kobayashi R, Mugishima H, Kato S
  • Journal Title: Mol. Genet. Metab Volume: 107 Pages: 513-20
  • Peer Reviewed
• [Presentation] Efficacy of oral administration of chloroquine on the neuronal cells of iduronate 2-sulfatatse gene knock-out mouse (2013)
  • Author(s): Tanaka A, Maeda M. Kadono C, Morimoto H.
  • Organizer: 第55回日本先天代謝異常学会
  • Place of Presentation: 千葉
  • Year and Date: 20131127-29
• [Presentation] Genotype-phenotype correlation and the antibody formation against idursulfase in the course of enzyme replacement therapy in mucopolysaccharidosis type II (2013)
  • Author(s): Hamazaki T, Tanaka A, Sawada T, Kadono C, Kudo S, Shintaku H.
  • Organizer: 第55回日本先天代謝異常学会
  • Place of Presentation: 千葉
  • Year and Date: 20131127-29
• [Presentation] Mugishima H, Kato S. Efficacy of hematopoietic stem cell transplantation versus enzyme replacement therapy on intelligence in the patients with mucopolysaccharidosis type II (2013)
  • Author(s): Tanaka A, Hamazaki T, Kosuga M. Okuyama T, Suzuki Y, Sakai N, Sawada T, Yabe H, Ishige M
  • Organizer: 第55回日本先天代謝異常学会
  • Place of Presentation: 東京
  • Year and Date: 20131127-29
• [Presentation] Pseudodeficiency alleleは意外に多く存在する? (2013)
  • Author(s): 田中あけみ,濱崎考史,鈴木健,奥山虎之,坂口知子,工藤聡志,門野千穂,藤川研人,小田絵里,藤直子,斎藤三佳,澤田智,北川照,桜庭均,斎藤靜司
  • Organizer: 日本人類遺伝学会第58回大会
  • Place of Presentation: 仙台
  • Year and Date: 20131120-23
• [Presentation] ムコ多糖症II型の酵素補充療法:遺伝子型と表現型の相関と抗イズルスルファーゼ抗体の産生について (2013)
  • Author(s): 濱崎考史、田中あけみ、澤田智、門野千穂、工藤聡志、新宅治夫
  • Organizer: 第58回日本人類遺伝学会
  • Place of Presentation: 仙台
  • Year and Date: 20131120-23
• [Presentation] Iduronate 2-sulfatase knock-out mouseにおける中枢神経病変の電子顕微鏡所見 (2013)
  • Author(s): 田中あけみ
  • Organizer: 第55回日本小児神経学会
  • Place of Presentation: 大分
  • Year and Date: 20130529-0601
• [Presentation] ムコ多糖症II型重症型の中枢神経障害に対する造血幹細胞移植と酵素補充療法の効果の比較 (2013)
  • Author(s): 田中あけみ、濱崎考史、酒井規夫、奥山虎之、鈴木康之、澤田智、大橋十也、大浦敏博、麦島秀雄、大友孝信
  • Organizer: 第55回日本小児神経学会
  • Place of Presentation: 大分
  • Year and Date: 20130529-0601
• [Presentation] Iduronate 2-sulfatase knock-out mouseにおける中枢神経病変の電子顕微鏡所見 (2012)
  • Author(s): 田中あけみ、前田光代、門野千穂、森本秀人
  • Organizer: 第54回日本先天代謝異常学会
  • Place of Presentation: 岐阜
  • Year and Date: 20121115-17
• [Presentation] Anti-Idursulfase Antibody and the Efficacy of Enzyme Replacement Therapy in the Patients with Mucopolysaccharidosis Typa II (2012)
  • Author(s): Tanaka A, Hamazaki T, Sawada T, Kadono C, Kudo S, Shintaku H.
  • Organizer: SSIEM 2012
  • Place of Presentation: Birmingham, England
  • Year and Date: 20120904-08
• [Presentation] Stabilization of Symptoms and Activity of Daily Living (ADL) in the Patients with Mucopolysaccharidosis Type II Received Hematopoietic Stem Cell Transplantation (2012)
  • Author(s): Tanaka A, Okuyama T, Suzuki Y, Sakai N, Takakura H, Sawada T, Tanaka T, Otomo T, Ohashi T, Wada M, Yabe H, Ohura T, Suzuki N, Kato K, Adachi S, Kobayashi R, Mugishima H, Kato S.
  • Organizer: 12^<th> International Symposium on MPS and Related Diseases
  • Place of Presentation: Noordwijkerhout, The Netherlands
  • Year and Date: 20120628-0701
• [Presentation] Anti-idursulfase Antibody and the Efficacy of Enzyme Replacement Therapy in Mucopolysaccharidosis Type II Patients (2012)
  • Author(s): Hamazaki H, Tanaka A, Sawada T, Kadono C, Kudo S, Shintaku H.
  • Organizer: 12^<th> International Symposium on MPS and Related Diseases
  • Place of Presentation: Noordwijkerhout, The Netherlands
  • Year and Date: 20120628-0701
• [Presentation] Newborn screening of Mucopolysaccharidosis I and II and Characterization of Pseudodeficiency Alleles of Iduronate 2-sulfatase Gene found in the Screening (2012)
  • Author(s): Tanaka A, Sawada T, Suzuki K, Sakuraba H, Saitou S, Sakaguchi T, Kitagawa T.
  • Organizer: 12^<th> International Symposium on MPS and Related Diseases
  • Place of Presentation: Noordwijkerhout, The Netherlands
  • Year and Date: 20120628-0701
• [Presentation] Pseudodeficiency Alleles of Iduronate 2-sulfatase Gene and the Structural Modeling of the Enzyme Protein (2012)
  • Author(s): Tanaka A, Sawada T, Suzuki K, Sakuraba H, Saitou S, Sakaguchi T, Kitagawa T.
  • Organizer: The 2^<nd> Asian Congress of Inherited Metabolic Diseases
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20120401-04
• [Presentation] Long-term efficacy of hematopoetic stem cell transplantation in the patients with mucopolysaccharidosis type II : a nationwide survey in Japan (2011)
  • Author(s): Tanaka A, Okuyama T, Suzuki Y, Sakai N, Takakura H, Sawada T, Tanaka T, Otomo T, Ohashi T, Wada M, Yabe H, Ohura T, Suzuki N, Kato K, Adachi S, Kobayashi R, Mugishima H, Kato S.
  • Organizer: Annual Meeting of Society for the Study of Inborn Errors of Metabolism 2011
  • Place of Presentation: Geneva, Switzerland
  • Year and Date: 20110829-0902
• [Book] ムコ多糖症II型。先天代謝異常ハンドブック (2013)
  • Author(s): 田中あけみ
  • Total Pages: 192-193(440)
  • Publisher: 中山書店
• [Book] ムコ多糖症。今日の神経疾患治療指針 (2013)
  • Author(s): 田中あけみ
  • Total Pages: 653-656(1100)
  • Publisher: 医学書院
• [Book] 先天性ムコ多糖症。内科学第10版 (2013)
  • Author(s): 田中あけみ
  • Total Pages: 1868-18722404
  • Publisher: 朝倉書店
• [Book] ムコ多糖症II型。「先天代謝異常症候群」(第2版)下巻:別冊日本臨床新領域症候群シリーズ (2012)
  • Author(s): 田中あけみ
  • Total Pages: 533-538
• [Book] Enzyme Replacement Therapy for Lysosomal Storage Dseases(Neurochemistry of Metabolic Disease) (2011)
  • Author(s): Tomatsu S, Montaño AM, Molano ACS, Roman D, Hintze J, Carvalho CG, Federhen A, Vieira TA, Giugliani R, Węgrzyn G, Tanaka A, Suzuki Y, Orii T. (Chaptor 8)
  • Total Pages: 129-158(301)
  • Publisher: Sanker Surendran, Nova Science Publishers, Inc
• [Book] ムコ多糖症、ムコリピドーシス。今日の小児治療指針第15版(総編集:大関武彦、古川満、横田俊一郎、水口雅) (2011)
  • Author(s): 田中あけみ
  • Total Pages: 210(1001)